Experimental Gerontology · Mar 27, 2019

Mitochondrial mRNA translation initiation contributes to oxidative metabolism in the myocardia of aged, obese mice

By Lee DE, Perry RA, Brown JL et al.

UNLABELLED: Being both advanced in age and obese each contribute to cardiac hypertrophy in a unique manner. Electron transport complexes I and IV are implicated in deficient electron transport during cardiomyopathies and contain the majority of protein subunits that are transcribed and translated by machinery localized within the mitochondria. PURPOSE: To assess myocardial mt-mRNA translation factors in relation to mitochondrial content and mtDNA-encoded protein using a mouse model of aged obesity and to test the relationship of mt-mRNA translation initiation factor 2 (mtIF2) to oxidative capacity and the cellular oxidation-reduction (redox) state in cardiomyocytes. METHODS: Male C56BL/6 J mice fed lean or high fat diet were aged to either ~3 months or ~22 months, the heart was excised and analyzed using immunoblot and qPCR to assess differences in mitochondrial mRNA translation machinery. Using H9c2 cardiomyocytes, mtIF2 was knocked-down and oxidative metabolic characteristics assessed including oxidation/reduction state, bioenergetic flux, and hypoxic resistance was tested. RESULTS: Aged, obese mouse hearts were ~40% larger than young, lean controls and contained ~50% less mtIF2 protein alongside ~25-50% lower content of Cytb, a protein encoded by mtDNA. Reducing the level of mtIF2 by shRNA is associated with ~15-20% lower content of OXPHOS complex I and IV, ~30% lower optical redox ratio, ~40% oxygen reserve capacity, and ~20% less cell survival following hypoxia. CONCLUSION: We present evidence of altered mt-mRNA translation during cardiac hypertrophy in aged obesity. We build on these results by demonstrating the necessity of mtIF2 in maintaining oxidative characteristics of cardiac muscle cells.

doi.org/10.1016/j.exger.2019.03.009PubMed 30928679Mechanisms